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Microfiche 
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Collection  de 
microfiches 
(monographies) 


Canadian  Institute  for  Historical  Microroproductions  /  Instltut  canadien  de  microroproductions  historiquos 


©1999 


V:.,  .'hca!  a.-!d  Bibliographic  Notes  /  Notes  techniques  et  bibliographiques 


The  Insti'L  "  '\.i-^  aitmpted  lo  obtain  the  best  original 
cooy  avf^.-.^hi^  for  '  I.iiing.  Features  of  this  copy  which 
may  be  brU  v^^.  aph'r  ally  unique,  which  may  alter  any  of 
the  images  in  ihe  reproduction,  or  which  may 
significantly  change  ifie  usual  method  of  filming  are 
checked  below. 


□ 

□ 

n 

n 
□ 

□ 


n 


Coloured  covers  / 
Couverture  de  couleur 

Covers  damaged  / 
Couverture  endommagee 

Covers  restored  and/or  laminated  / 
Couverlure  restauree  eu'ou  pelliculee 

Cover  title  missing  /  Le  titre  de  couverture  m.anque 

Coloured  maps  /  Cartes  geographiques  en  couleur 

Coloured  ink  (i.e.  other  than  blue  or  black)  / 
Encre  de  couleur  (i.e.  autre  que  bleue  ou  noire) 

Coloured  plates  and/or  illustrations  / 
Planches  et/ou  illustrations  en  couleur 

Bound  with  other  material  / 
Relie  avec  d'autres  documents 

Only  edition  available  / 
Seule  edition  disponible 

Tight  binding  may  cause  shadows  or  distortion  along 
interior  margin  /  La  reliure  serree  peut  causer  de 
I'ombre  ou  de  la  distorsion  le  long  de  la  marge 
interieure. 

Blank  leaves  added  during  restorations  may  appear 
within  the  text.  Whenever  possible,  these  have  been 
omitled  from  filming  /  ll  se  peut  que  certaines  pages 
blanches  ajoutees  lors  d'une  restauraticn 
apparaissent  dans  le  texte.  mais,  lorsque  cela  etait 
possible,  ces  pages  n'ont  pas  ete  filmees. 

Additional  comments  / 
Commcntaires  supplementaires: 


L'Institut  a  microfilme  le  rneilleur  exemplaire  qu'il  lui  a 
ete  possible  de  se  procurer.  Les  details  de  cet  exem- 
plaire qui  sont  peut-etre  uniques  du  point  de  vue  bibli- 
ographique,  qui  peuvenf  modifier  une  image  reproduite. 
ou  qui  peuvent  exiger  une  modification  dans  la  metho- 
de  normaie  de  filmage  sont  indiques  ci-dessous. 

I  Coloured  pages  /  Pages  de  couleur 

I I    Pages  damaged  /  Pages  endommagees 


D 


Pages  restored  and/or  laminated  / 
Pages  restaurees  et/ou  pelliculees 


I      1    Pages  discoloured,  stained  or  foxed  / 
L — I    Pages  decolorees,  tachetees  ou  piquees 

Pages  detached  /  Pages  detachees 

I    Shov;1hrough /Transparence 


Quality  of  print  varies  / 
Qualite  inegale  de  I'impressicn 


Includes  supplementary  material  / 
-    Comprend  du  materiel  supplem,entaire 


D 


Pages  wholly  or  partially  obscured  by  errata  slips, 
tissues,  etc.,  have  been  refilmed  to  ensure  the  best 
possible  image  /  Les  pages  totalement  ou 
parliellement  obscurcies  par  un  feuillet  d'errata,  une 
pelure,  etc.,  onf  ete  filmees  a  nouveau  de  faijon  a 
obtenir  la  meilleure  image  possible. 

Opposing  pages  with  varying  colouration  or 
discolourations  are  filmed  twice  to  ensure  the  best 
possible  image  /  Les  pages  s'opposant  ayant  des 
colorations  variables  ou  des  decolorations  sont 
filmees  deux  fois  afm  d'obtenir  la  meilleure  image 
possible. 


This  Item  is  filmed  at  the  reduction  ratio  checked  below  / 

Ce  document  est  tilme  «u  tnu»  de  reduction  mrliquo  ci  dessous 


10x 


14x 


iex 


22x 


26x 


30x 


12x 


16x 


20x 


24x 


28x 


32x 


The  copy  filmed  here  has  been  reproduced  thanks 
to  the  generosity  of: 

J.J.  Talman  Regional  Collection 
D.B.  Weldon  Library 
University  of  Western  Ontario 

This  title  was  microfilmed  with  the  generous 
permission  of  the  rights  holder: 


L'  exemplaire  filme  fut  reproduit  grace  a  la 
generosite  de: 

J.J.  Talman  Regional  Collection 
D.B.  Weldon  Library 
University  of  Western  Ontario 

Ce  litre  a  ete  microfilme  avec  I'aimable  autorisation 
du  detenteur  des  droits: 


Kenneth  Lasson 


Kenneth  Lasson 


The  images  appearing  here  are  the  best  quality 
possible  considering  the  condition  and  legibility  of 
the  original  copy  and  in  keeping  with  the  filming 
contract  specifications. 

Original  copies  in  printed  paper  covers  are  filmed 
beginning  with  the  front  cover  and  ending  on  the 
last  page  with  a  printed  or  illustrated  impression,  or 
the  back  cover  when  appropriate.  All  other  original 
copies  are  filmed  beginning  on  the  first  page  with  a 
printed  or  illustrated  impression,  and  ending  on  the 
last  page  with  a  printed  or  illustrated  impression. 


The  last  recorded  frame  on  each  microfiche  shall 
contain  the  symbol  -»(meaning  "CONTINUED"),  or 
the  symbol  V  (meaning  'END"),  whichever  applies. 

Maps,  plates,  charts,  etc.,  may  be  filmed  at 
different  reduction  ratios.   Those  too  large  to  be 
entirely  included  in  one  exposure  are  filmed  begin- 
ning in  the  upper  lefi  hand  corner,  left  to  right  and 
top  to  bottom,  as  many  frame.'^  as  required    The 
foil  jwing  diagrams  illustrate  the  method. 


1  2  3 


Les  imo^es  suivantes  ont  ete  reproduites  avec  le 
plus  grand  soin,  compte  tenu  de  la  condition  et  de 
la  nettete  de  I'exemplaire  filme,  et  en  conformite 
avec  les  conditions  du  contrat  de  fHmage. 

Les  exemplaires  originaux  dont  la  couverture  en 
papier  est  imprimee  sont  filmes  en  commengant 
par  le  premier  plat  et  en  terminant  soit  par  la 
derniere  page  qui  comporte  une  empreinte  d'im- 
pression  ou  d  illustration,  soit  par  le  second  plat, 
selon  le  cas.   Tqus  les  autres  exemplaires  origin- 
aux sont  filmes  en  commenijant  par  la  premiere 
page  qui  comporte  une  empreinte  d'impression  ou 
d'lllustration  et  en  terminant  par  la  derniere  page 
qui  comporte  une  telle  empreinte. 

Un  des  symboles  suivants  apparaitra  sur  la 
derniere  image  de  chaque  microfiche,  selon  le  cas: 
le  symbole  -»  signifie  "A  SUIVRE",  le  symbole  V 
signifie  "FIN" 

Les  cartes,  planches,  tableaux,  etc.,  peuvent  etre 
filmes  a  des  taux  de  reduction  differents    Lorsque 
le  document  est  trop  grand  pour  etre  reproduit  en 
un  seul  cliche,  il  est  filme  a  partir  de  Tangle 
supeneur  gauche,  de  gauche  a  droite,  et  de  haut 
en  bas,  en  prenant  le  nombre  d  images 
necessaire.   Les  diagrammes  suivants  illustrent  la 
methode. 


1 

2 

3 

4 

5 

6 

MICROCOPY    RESOLUTION    TEST    CHART 

ANSI  una  ISO  TEST  CHART  No    2 


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^     .APPLIED  INA^DE     Inc 


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I    IL^ 


\   The  Standardization  of   Digitalis 
and  the  Potency  of  American- 
Grown   Digitalis 


I.     1 ,     k  ( >  w  \  r  u  i:  v .    \\  \y 

M  I  X  \i;  \l'nl,l> 
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it  \i.ri  MdKi: 


//.'r  Jiifival  oi   the  Amcruan   Mciiwnt  Assmiaiwii 

Mif.ii  1,1.  1116.  Vol.  i.sri.  rr-  ■*'""  «"■'  •<'' 


Ami  .  .    •.-.    .'.iKiPii  \i    A--i'fiATii>\ 
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The    Standardization    of    Digitalis 
and  the  Potency  of  American- 

¥ 

Grown  Digitalis 


i.    (i     ROW  X  r  R  i:  I-.    Ml) 

\|  I  XM  Arii|.|> 
A  X  I  > 

1)      I.      M  At    ir|-.      .M.I), 
i:  \i;n  \i()Ki: 


THK      STANDARDIZAI  lOX      Ol"      DKIllALIS 
AND   Tin-:   PO  TF XC  Y   OF  AMKRICAX- 

(;ro\vx    i^ir.riAi.is* 


L.    G.     ROWNTRKH,    M.D. 

MINNEAPOLIS 
AND 

D.    I.    MACJIT,    M.D. 

nAI.TIMORE 


This  study  was  undertaken  by  us,  at  the  suggestion 
of  Dr.  Janeway,  in  the  endeavor  to  insure  digitalis 
preparations  of  maximum  and  known  efTectiveness  for 
use  in  the  wards.  These  desiderata  are  so  rarely  ful- 
filled in  any  hospital  that  the  results  we  have  obtained 
seem  worthy  of  a  brief  report. 

MKTIIiiDS     OF     STANDARDIZATION 

Two  methods  of  biologically  standardizing  digitalis 
preparations  are  commonly  employed:  the  so-called 
"frog"  method,  and  the  so-called  "cat"  method.  After 
a  number  of  preliminary  experiments  it  was  found  that 
the  frog  method  was  less  reliable  for  the  standardiza- 
tion of  the  infusion  than  the  cat  methods  the  latter 
method  was  therefore  exclusively  employed  in  this 
work.  The  technic  followed  by  us  was  suggested  by 
Hatcher  and  Brody,^  and  is  somewhat  similar  ':o  that 
described  by  them,  and  consisted  in  determining  the 
minimal  fatal  dose  per  kilogram  weight  of  cat,  the 
drug  being  injected  slowly  into  the  femoral  vein.  Our 
procedure  was  briefly  as  follows: 

A  heahhy  cat  was  anesthetized  witli  ether,  and  a  cannula 
inserted  into  a  femoral  vein,  suhscquently  a  minimum  amount 
of  ether  being  administered,  just  sufficient  to  keep  the  animal 


*  From  the  Medical  Clinic  of  the  Johns  Hopkins  Hospital,  and 
Pharmacological   Laboratory   of   the   Johns   Hopkins   University. 

1.  It  is  advisable  to  m.ike  three  toxicity  experiments  with  each 
I  reparation  and  to  take  the  average.  As  a  rule  wide  variations  are  not 
encountered. 

2.  Hatcher  and   Brody:  Am.  Jour.   Pharm.,  1910,  lxx.\ii,  360. 


qtiict.  Ten  c  c.  of  the  itifusion  of  digitali'^  were  slnwly 
injected  into  the  vein  in  the  course  of  five  minutes,  and  there- 
after 1  c.c.  every  two  niiinitcs  until  the  death  of  the  animal. 
The  total  amount  of  the  druR  injected  divided  hy  the  weigiit 
of  the  animal  pave  tlic  strenKth  of  the  preparation  in  tirms 
of  so-called  "cat  nnif.."  The  following  protocol  will  serve 
as  an  illustration  : 

F.xpcrinicnt.  April  30,  1015.     Cat  weighing  2.f)  kg.     ("annula 
in  left  femoral  vein,  light  ether  anesthesia. 

.1:20  p.  m.  experiment  begins.    Pulse  160  per  min. 

Slow  injection  uf  infusioii  digitalis. 


.  liiiihlicil    iiijti  tiuii   of    10  c'.< 
1   c. 


,1:27 InjpclCil 

.1:29    Injected 

.V.II Tiijerted 

?:?^ Injected 

,1  :.1S  ,  , Injected 

.1  :.ir Injected 

^■.y> In'ectcd 

,1:41 Injected 

3:4.1 Injected 

3:45 Injected 

3  :4r Injected 

3:4') Injected 

.1  :.~1 InjcctPil 

3:53 Injected 

3:55 Injected 

3:57 Injectett 

3  :.^9 Injected 

'rnt:d    aiiinnnt    of    infnfir>n     — 
Tlurrfore    Ictli.il    dusc  -- 


.  .Pulse   1 10  [ler    niiniitc 
.  .Pulse   120 

1  c.i Pulse  inn 

1   c.c Pulse  72   rcspir.itinns     rii'id 

1   c.c Pu'se     72   vtnuits 

1   c.c Pulse     72 

1   c.c Pulse  60 

1  c.c Pulse  14.S 

1   c.c Pulse  160 

1   c.c Pulse  160 

1  c.c Pulse  I.SO 

1  c.c Pul.se  168 

1  c.c Pulse  240 

1   c.r Pulse  240 

1   c.c Pulse  240 

1    CA Pulse  irrCKul  ir,    very    iiiiid 

1    c.c Pulse  irrrcnl.ir,    very    rapul 


1    c.c Pulse  dc 

.^11  c.c. 


id:    li(,irt    in    systole 


2.6  10  c.c.  per  kj.- 

I'lV  this  luclhud  dillcrciil  infusions  of  digitalis  pre- 
pared from  two  batches  of  Allen's  English  leaves  were 
assayed:  the  one  from  the  stock  of  the  pharmacy  of 
the  Johns  Hopkins  Hospital,  the  other  an  infusion 
])rocurcd  from  a  well-known  pharmacy  in  New  York. 
The  lethal  dose  of  the  former  was  found  to  be  13.5  c.c. 
per  kilogram;  that  of  the  latter,  7.5  c.c.  per  kilogram. 
This  difference  in  potency  could  be  accounted  for  only 
in  two  ways :  cither  by  dilTercnces  in  the  method  of 
jircparation  or  by  variations  in  the  intrinsic  quality  of 
the  leaves. 


DIFFEREXCi:S    IN    POTENCY    DUE    TO    METHOD 
OF     PREPARATION 

A  comparison  was  made  between  a  New  York  infu- 
sior.  of  digitalis  and  an  infusion  from  the  same  stock 
of  leaves  ])repared  by  our  own  pharmacist.  The  lethal 
ildse  of  the  New  York  preparation  wa ".  6.6  c.c.  per 
The  lethal  dose  of  our  O'.mi  infusion  froai 


/ 


tlir  >.imc  kavcs  was  9  c.c.  per  kil()<,'rani.  I'uur  days 
latrr  the  -anic  prciiaratioiis,  having  been  kept  on  ice, 
were  rc>taiiikir(li/C(i,  and  f,'avc  •'"  '"hal  doses  of 
().S  r.c.  and  9  c.c.  per  kilogran:,  re  -••vely,  showing 
that  the  preparation  did  not  dete.i< irate  rapidly  on 
-landing,  a  fact  which  has  hccn  pui.Ucd  out  recently 
by  I  lately  r 

These  ligurcs  uidicated  clearly  a  difference  in 
])otency  due  to  the  met'iod  of  preparation.  The  New 
Vork  technic  for  preparing  he  infusion  was  then 
ascertained^  and  applied  to  our  own  stock  of  English 
leaves.  The  lethal  dose  of  this  infusion  was  found  to 
be  11.1  c.c.  per  kilogram  of  cat.  An  infusion  made 
from  the  same  leaves  by  the  method  formerly  employed 
by  our  pharmacist  gave  a  lethal  dosage  of  13.5  c.c. 

In  order  to  ascertain  still  further  how  great  a  differ- 
ence in  potency  of  infusions  may  result  from  varia- 
tions in  the  methods  of  preparing  them,  our  pharma- 
cist, Dr.  Wahl.  prepared  three  infusions  from  the  same 
lot  of  Allen's  English  leaves,  by  slightly  different  phar- 
maceutic nietboiis.  Infusion  1  was  ])repared  accord- 
ing to  the  U.  S.  Pharmacopeia.*  Infusion  2  was  made 
by  macerating  the  leaves  with  water  plus  10  jicr  cent, 
dilute  alcohoi,  iristcad  of  adding  the  alcfihol  to  the 
fmished  product  as  directed  in  the  U.  S.  Pharmacopeia. 
Infusion  3  was  pre|)ared  bv  macerating  tlie  leaves  with 
boiling  water  in  a  closed  flask,  and  gently  beating  the 
contents  of  the  flask  during  tlie  whole  jirocess  of 
extraction.  The  lethal  dose  of  Infusion  1  was  found 
to  be  11.4  c.c,  that  of  Infusion  2,  9.5  c.c,  and  that  of 
Infusion  3,  10.6  c.c.  iicr  kilogram  weight  of  cat.  Thus 
it  will  be  seen  that  a  considerable  variation  in  the 
|)otency  of  an  infusion  of  digitalis  may  result  from 
(lifTerences  in  methods  of  preparation. 


I 


V.MU.XTIONS   niT.   TO   TIIK   SOrRCE   OF   Tiir,    i.E.wr.s 

The  (liiTerence  in  the  potency  between  the  New  York 
infusion  and  our  infusions  just  described  could  not  be 
entirely  explained  by  variations  in  the  method  of  prep- 
aration, but  were  also  obviously  due  to  differences  in 


3.  The  method  nf  rrep.iring  the  infusion  employed  at  Johns  Honkin« 
is  the  offici.ll  method  of  th-  U:  S.  P.  The  New  York  technic  differed 
from   this   in   some   details   which   need   not   be   gone   into   in   this  place. 

4.  AlthouRh  the  U.  S.  P.  gives  specific  direction  for  preparing  the 
infusion  of  d-gitalis,  we  have  good  reason  to  believe  that  those  directions 
are  not  always  followed.  Compare  Alpcrs;  Jour,  of  Am.  Pharmaceut. 
Assn.,  June,  1915,  p,  715. 


the  inherent  (luahlies  of  the  leaves  used.  Tlic  next 
step  in  the  investifjation  was  therefore  to  assay  infu- 
sions of  (hgitahs  prepared  by  a  uniform  method  from 
various  lots  of  (hgitalis  leaves  obtained  from  various 
sources.  Great  variations  in  the  strength  of  the 
products  were  noted. 

It  was  found  tliat  an  infusion  prepared  according  to 
the  U.  S.  rharniac()])eia  from  our  stock  of  English 
leaves  yielded  a  j)roduct  with  the  lethal  dose  of  13.5  c.c. 
That  of  an  infusion  from  another  lot  of  English  leaves 
was  found  to  be  9.6  c.c,  while  still  another  lot  of 
English  leaves  yielded  an  infusion,  the  lethal  dose  of 
whicli  was  8.7  c.c.  per  kilogram.  An  infusion  pre- 
pared from  some  (jcrman  digitalis  leaves  found  in  the 
iiospital  ])harmacy  ,ir'^ved  very  inferior  in  quality,  giv- 
ing a  letlial  dose  of  19  c.c.  per  kilogram  weight. 

rOTKXCV     OF     .\MK.RK.\N     I.i:.\VKS 

It  was  especiallv  interesting  to  fuid  that  certain 
American  grown  digitalis  leaves  yielded  a  product  of 
a  very  higli  (|uality.  Two  lots  of  .\nierican  leaves 
were  as:;aved  l)v  us.  One  was  a  .■Mpi)ly  of  Wisconsin 
leaves  kindly  ])rcsented  by  Dr.  (jeorge  B.  Roth  of  the 
Ilvgienic  Labor.i'or'  'm  Washington.  The  second  was 
obtained  from  Dr.  i.  Krcmers  of  the  Pharmaceutical 
h'xperiment  Station,  University  of  Wisconsin.  The 
first  yielded  an  infusion  with  a  lethal  dose  of  7.6  c.c, 
and  the  second  an  infusion  with  a  potency  of  7.8  c.c. 
per  kilogram  weight  of  cat.  It  is  evident  that  both 
iiit'usinns  made  from  the  American  grown  leaves  were 
-.uperior  in  potcncx  to  tlio^e  made  troni  our  stock 
i'.nglisb  and  ( icmian  leaves,  and  in  fact  •-u]ierior  to  all 
other  le.ivc<  a>sa\ed  liy  ii-.  We  liave  in  America, 
ibercforc.  ;i  digitalis  wliicb  !•-  unsur|iassc(l,  Tlu-ougb 
tiie  kindne--->  ot'  Dr.  Kremers  a  -»upi)ly  ol  W  i-consin 
Ic.iM's  \\,iv  '-ccinc'i  au'l  i-^  now  being  u-cd  exclusively 
ill  the  w.irds  ot'  the  Jolm^  llo]ikins  llo'>pit,il. 


1  II  I      MOK  \i. 

riicM'  in\ c-tig.itioiH  s!rikiiij.;!\  em|iba'-i/c  llu'  iiitii 
111'  -landardi/atioii  of  digitali--.  Xav.ilion^  in  Utb.il 
(|o-e  trmn  ().()  to  1")  cc  per  kilogram  weight  -  ,ii)proxi 
in.inb  .>(K)  per  cent,  were  (ouikI  m  infii-ioiis  pre- 
pared I'roni  tiicsc  N.irioii^  li.ive^.  Certainly  this  is 
guaicr    than    ■~liould    be    tolrraled    by    liie    profct-sion. 


S'ct  in  all  ])rul)al)ilit\  still  i,n-fatiT  variati(jns  cxi^t  in 
liavf>  |)nroliasi'(l  in  tlu'  oi^-n  niarkel. 

Standarilization  reveals  the  strength  of  the  digitalis 
lireparatioii  and  permits  of  graded  dosage  —  more  or 
less  —  according  to  the  potency  of  the  preparation, 
jhe  physician's  duty  to  his  patient  does  not  end  with 
the  prescribing  of  digitalis.  Plainly  it  is  incumbent  on 
him  to  secure  digitalis  effects  if  the  case  is  a  suitable 
one.  This  is  more  likely  to  be  acconi])l!shed  if  the 
potency  of  the  ])re])aration  is  known. 

We  are  a'so  brought  face  to  face  with  another  fact, 
that  the  name  of  this  or  that  fnni  does  not  always 
insure  ])Otency  or  digitalis  effect.  .\s  we  have  shown, 
American  leaves  can  lie  secured  which  are  unsurpassed. 
The  answer  to  the  (luestion  of  potency  is  to  be  found 
in  standardization,  which  is  essential  to  the  best  treat- 
ment. 


